Bispecific molecules cross-linking ITIM and ITAM for therapy

Abstract

The invention includes bispecific molecules capable of cross-linking ITAM and ITIM receptors on a cell in order to inhibit cell activation, as well as gene therapy approaches using nucleotides encoding such bispecific molecules for expression in vivo. One example of an ITAM/ITIM receptor pair is FcεRI and HM 18 , and another is FcεRI and FcγRII. Cross-linking of these receptors with a bispecific molecule of the invention would lead to inhibition of the release of allergic mediators and amelioration of the symptoms of allergic diseases. Other diseases can be ameliorated by cross-linking ITIM/ITAM receptor pairs.

1. A bispecific antibody, or a binding fragment thereof, comprising a first determinant that binds to an Immunoreceptor Tyrosine-Based Activation Module (ITAM), wherein said ITAM is selected from the group consisting of BCR, FcεRI, FcγRI, FcγRIIA, FcγRIIIA, and TCR, and a second determinant that binds to an Immunoreceptor Tyrosine-Based Inhibition Module (ITIM), wherein the ITIM is FcεRII. 
     
     
       2. The bispecific antibody of  claim 1 , wherein at least one determinant is humanized, human, chimeric, or an ScFv. 
     
     
       3. A method of inhibiting the release of TNF-α from a mast cell or a basophil comprising administering the bispecific antibody, or a binding fragment thereof, of  claim 1 , wherein said ITAM is FcεRI, FcγRI, FcγRIIA, or FcγRIIIA. 
     
     
       4. A method of inhibiting the release of histamine from a mast cell or a basophil comprising administering the bispecific antibody, or a binding fragment thereof, of  claim 1 , wherein said ITAM is FcεRI, FcγRI, FcγRIIA, or FcγRIIIA. 
     
     
       5. A method of ameliorating an allergic disease or condition in a mammal comprising administering the bispecific antibody, or a binding fragment thereof, of  claim 1 . 
     
     
       6. The method of  claim 5 , wherein the bispecific antibody is administered at a concentration range from 0.1 to 1 μg/ml. 
     
     
       7. A composition comprising the bispecific antibody, or a binding fragment thereof, of  claim 1 , and a physiologically acceptable carrier, excipient, or diluent. 
     
     
       8. A method of ameliorating an allergic disease or condition in a mammal comprising administering the composition of  claim 7 . 
     
     
       9. A method of inhibiting the release of TNF-α from a mast cell or a basophil comprising administering the composition of  claim 7 , wherein said ITAM is FcεRI, FcγRI, FcγRIIA, or FcγRIIIA. 
     
     
       10. A method of inhibiting the release of histamine from a mast cell or a basophil comprising administering the composition of  claim 7 , wherein said ITAM is FcεRI, FcγRI, FcγRIIA, or FcγRIIIA.